Paclitaxel (Taxol), a diterpene taxane compound, is a natural product extracted from the bark of the Pacific yew tree, Taxus Brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis during the cell cycle. Taxol has recently been approved for the treatment of refractory advanced ovarian cancer, breast cancer and most recently, AIDS-related Kaposi's Sarcoma. The results of paclitaxel clinical studies are replete in scientific periodicals and have been reviewed by numerous authors, such as Rowinsky and Donehower in The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Phamac. Ther., 52, pp. 35-84 (1991); Spencer and Faulds, Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer, Drugs, 48 (5), pp. 794-847 (1994); K. C. Nicolau et al., Chemistry and Biology of Taxol, Angew. Chem., Int. Ed. Eng., 33, pp. 15-44 (1994); F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, and V. Valero, "Taxane Anticancer Agents--Basic Science and Current Status", edited by Gunda I Georg, Thomas C. Chen, Iwao Ojima, and Dolotrai M. Vyas, pp. 31-57 American Chemical Society, Wash., D.C. (1995); Susan G. Arbuck and Barbara Blaylock, "Taxol.RTM. Science and Applications", edited by Matthew Suffness, pp. 379-416, CRC Press, Boca Raton, FL (1995) and the references cited therein.
A semi-synthetic analog of paclitaxel named Taxotere.RTM. (docetaxel) has lso been found to have good antitumor activity. The structures of Taxol and Taxotere are shown below along with the conventional numbering system for molecules belonging to the Taxane class; such numbering system is also employed in this application. ##STR1##
Taxol.RTM. (paclitaxel): R=Phenyl; R'=acetyl, 2 PA1 Taxotere.RTM.: R=t-butoxy; R'=hydrogen
With reference to the numbering of the taxane, reference to a particular carbon on the taxane structure shall be indicated throughout this application by a "C-number", which signifies the carbon on the taxane according to the above numbering system. For example, "C-13" refers to the carbon at position 13 on the taxane ring as shown above, having a sidechain coupled thereto. Additionally, numerals in bold type following compound names and structures refer to the compounds illustrated in the prior art paclitaxel syntheses and Schemes 1-3, hereinbelow
The central backbone structural unit of paclitaxel is Baccatin III 1, a diterpenoid having the chemical structure: ##STR2##
It is also very similar in structure to 10-deacetylbaccatin III 3 ("10-DAB"), which has the chemical structure: ##STR3##
but which lacks an acetate ester at the 10-position alcohol.
Commercial pharmaceutical products containing paclitaxel are available, e.g. for the treatment of ovarian and breast cancer, and most recently, AIDS-related Kaposi's Sarcoma. Paclitaxel has also shown promising results in clinical studies for the treatment of other cancers. As a result, the demand for paclitaxel continues to escalate, and ever increasing amounts of paclitaxel are needed with each passing year for continued research and clinical studies. Paclitaxel is extracted with difficulty and in low yields for the bark of Taxus brevifolia (approximately 1 kg. of the drug is isolated from the bark of 3,000 T. brevifolia trees). Because of the difficulty in extracting adequate yields, alternative sources for synthesizing paclitaxel are needed.
10-DAB is currently the starting material for the semi-synthesis of paclitaxel, and may be readily extracted from the needles and twigs of the European Yew tree, Taxus baccata L. Baccatin III, 10-DAB and other taxane compounds, do not, however, exhibit the degree of anti-tumor activity demonstrated by paclitaxel. Accordingly, the semi-synthesis of paclitaxel from baccatin III, 10-DAB and other taxane compounds is of great interest and importance.
The structural similarity of 10-DAB to taxol belies, however, the difficulty in converting 10-DAB into taxol, and in fact renders this conversion highly problematical. The required differentiation of the similarly reactive C-7 and C-10 hydroxyl functions and the selective esterification of the difficulty accessible C-13 hydroxyl group with the bulky and suitably protected N-benzoylphenylisoserine (.beta.-amido ester) sidechain of taxol, in practice, can be achieved only with specific protecting groups and under specially developed reaction conditions. J. N. Denis et al., A Highly Efficient, Practical Approach to Natural Taxol, J. Am. Chem. Soc. 110, pp. 5917-5918, 1988. This esterification at C-13 is a coupling reaction step which, although tedious due to its location within the concave region of the hemispherical taxane skeleton and because of significant steric hindrance around this position and by hydrogen bonding between the 13-hydroxyl and the 4-acetoxyl group, is a key step required in every contemplated synthesis of taxol or biologically active derivative of taxol, as the presence of the sidechain at C-13 is required for anti-tumor activity. Wani et al., J. Am. Chem. Soc. 93, pp. 2325 (1971).
Synthetic methods have been previously disclosed in scientific and patent literature. Three different routes for synthesizing paclitaxel known in the literature are discussed hereinbelow. The first two routes utilize 7-O-TES (triethylsilyl) accatin III 4, obtained from the selective silylation and cetylation of 10-DAB.
First Route of Paclitaxel Synthesis--Prior Art ##STR4##
The first route, developed by Professor R. A. Holton and disclosed in U.S. Pat. No. 5,274,124, which is incorporated by reference herein, reacts the lithium anion of 7-O-TES-baccatin III 4 with a .beta.-lactam to introduce the required paclitaxel amino acid sidechain at the C-13 position. The 7-O-TES protected baccatin III 4 can be obtained as described by Greene et al in J. Am. Chem. Soc. 110, pp. 5917 (1988).
Second Route of Paclitaxel Synthesis--Prior Art ##STR5##
The second route developed by Bristol-Myers Squibb and disclosed in U.S. patent application Ser. No. 07/995,443 and by D. G. I. Kingston et al., in Tetrahedron Letters 35, p. 4483 (1994), both of which are incorporated by reference herein, couples the 7-O-TES-baccatin III 4 with oxazolinecarboxylic acid 5 using DCC or a similar dehydrating agent.
Third Route of Paclitaxel Synthesis--Prior Art ##STR6##
A third route of synthesizing paclitaxel from 10-DAB and which couples 7-O-TROC baccatin III 6 with a protected .beta.-phenylisoserine sidechain 7, was developed by A. Commercon et al at Rhone-Poulenc Rorer. A. Commergon et al., Tetrahedron Letters 33, pp. 5185-5188 (1992). This route, however, while producing a significant amount of Taxotere, produces Taxol in much lesser yields.
The use of baccatin III as a starting material would significantly simplify the semisynthesis of paclitaxel. Baccatin III is currently being synthesized by cell culture and could become available in quantities sufficient to support economical and competitive semisynthesis. This would eliminate the need for 10-DAB in the semisynthesis of paclitaxel.